Endosomal phosphatidylinositol 3-phosphate controls synaptic vesicle cycling and neurotransmission.

Neural circuit function requires mechanisms for controlling neurotransmitter release and the activity of neuronal networks, including modulation by synaptic contacts, synaptic plasticity, and homeostatic scaling. However, how neurons intrinsically monitor and feedback control presynaptic neurotransmitter release and synaptic vesicle (SV) recycling to restrict neuronal network activity remains poorly understood at the molecular level. Here, we investigated the reciprocal interplay between neuronal endosomes, organelles of central importance for the function of synapses, and synaptic activity. We show that elevated neuronal activity represses the synthesis of endosomal lipid phosphatidylinositol 3-phosphate [PI(3)P] by the lipid kinase VPS34. Neuronal activity in turn is regulated by endosomal PI(3)P, the depletion of which reduces neurotransmission as a consequence of perturbed SV endocytosis. We find that this mechanism involves Calpain 2-mediated hyperactivation of Cdk5 downstream of receptor- and activity-dependent calcium influx. Our results unravel an unexpected function for PI(3)P-containing neuronal endosomes in the control of presynaptic vesicle cycling and neurotransmission, which may explain the involvement of the PI(3)P-producing VPS34 kinase in neurological disease and neurodegeneration.

Disruption of the rice 4-DEOXYOROBANCHOL HYDROXYLASE unravels specific functions of canonical strigolactones.

Strigolactones (SLs) regulate many developmental processes, including shoot-branching/tillering, and mediate rhizospheric interactions. SLs originate from carlactone (CL) and are structurally diverse, divided into a canonical and a noncanonical subfamily. Rice contains two canonical SLs, 4-deoxyorobanchol (4DO) and orobanchol (Oro), which are common in different plant species. The cytochrome P450 OsMAX1-900 forms 4DO from CL through repeated oxygenation and ring closure, while the homologous enzyme OsMAX1-1400 hydroxylates 4DO into Oro. To better understand the biological function of 4DO and Oro, we generated CRISPR/Cas9 mutants disrupted in OsMAX1-1400 or in both OsMAX1-900 and OsMAX1-1400. The loss of OsMAX1-1400 activity led to a complete lack of Oro and an accumulation of its precursor 4DO. Moreover, Os1400 mutants showed shorter plant height, panicle and panicle base length, but no tillering phenotype. Hormone quantification and transcriptome analysis of Os1400 mutants revealed elevated auxin levels and changes in the expression of auxin-related, as well as of SL biosynthetic genes. Interestingly, the Os900/1400 double mutant lacking both Oro and 4DO did not show the observed Os1400 architectural phenotypes, indicating their being a result of 4DO accumulation. Treatment of wild-type plants with 4DO confirmed this assumption. A comparison of the Striga seed germinating activity and the mycorrhization of Os900, Os900/1400, and Os1400 loss-of-function mutants demonstrated that the germination activity positively correlates with 4DO content while disrupting OsMAX1-1400 has a negative impact on mycorrhizal symbiosis. Taken together, our paper deciphers the biological function of canonical SLs in rice and reveals their particular contributions to establishing architecture and rhizospheric communications.

Abscisic acid inhibits germination of Striga seeds and is released by them likely as a rhizospheric signal supporting host infestation.

Seeds of the root parasitic plant Striga hermonthica undergo a conditioning process under humid and warm environments before germinating in response to host-released stimulants, particularly strigolactones (SLs). The plant hormone abscisic acid (ABA) regulates different growth and developmental processes, and stress response; however, its role during Striga seed germination and early interactions with host plants is under-investigated. Here, we show that ABA inhibited Striga seed germination and that hindering its biosynthesis induced conditioning and germination in unconditioned seeds, which was significantly enhanced by treatment with the SL analog rac-GR24. However, the inhibitory effect of ABA remarkably decreased during conditioning, confirming the loss of sensitivity towards ABA in later developmental stages. ABA measurement showed a substantial reduction of its content during the early conditioning stage and a significant increase upon rac-GR24-triggered germination. We observed this increase also in released seed exudates, which was further confirmed by using the Arabidopsis ABA-reporter GUS marker line. Seed exudates of germinated seeds, containing elevated levels of ABA, impaired the germination of surrounding Striga seeds in vitro and promoted root growth of a rice host towards germinated Striga seeds. Application of ABA as a positive control caused similar effects, indicating its function in Striga/Striga and Striga/host communications. In summary, we show that ABA is an essential player during seed dormancy and germination processes in Striga and acts as a rhizospheric signal likely to support host infestation.

SLHSD: hybrid scaffolding method based on short and long reads.

In genome assembly, scaffolding can obtain more complete and continuous scaffolds. Current scaffolding methods usually adopt one type of read to construct a scaffold graph and then orient and order contigs. However, scaffolding with the strengths of two or more types of reads seems to be a better solution to some tricky problems. Combining the advantages of different types of data is significant for scaffolding. Here, a hybrid scaffolding method (SLHSD) is present that simultaneously leverages the precision of short reads and the length advantage of long reads. Building an optimal scaffold graph is an important foundation for getting scaffolds. SLHSD uses a new algorithm that combines long and short read alignment information to determine whether to add an edge and how to calculate the edge weight in a scaffold graph. In addition, SLHSD develops a strategy to ensure that edges with high confidence can be added to the graph with priority. Then, a linear programming model is used to detect and remove remaining false edges in the graph. We compared SLHSD with other scaffolding methods on five datasets. Experimental results show that SLHSD outperforms other methods. The open-source code of SLHSD is available at https://github.com/luojunwei/SLHSD.

Aqueous extract of Descuraniae Semen attenuates lipopolysaccharide-induced inflammation by inhibiting ER stress and WNK4-SPAK-NKCC1 pathway.

Sepsis causes systemic inflammatory responses and acute lung injury (ALI). Despite modern treatments, sepsis-related ALI mortality remains high. Aqueous extract of Descuraniae Semen (AEDS) exerts anti-endoplasmic reticulum (ER) stress, antioxidant and anti-inflammatory effects. AEDS alleviates inflammation and oedema in ALI. Sodium-potassium-chloride co-transporter isoform 1 (NKCC1) is essential for regulating alveolar fluid and is important in ALI. The NKCC1 activity is regulated by upstream with-no-lysine kinase-4 (WNK4) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). This study aimed to investigate the effects of AEDS on lipopolysaccharide (LPS)-induced ALI model in A549 cells, considering the regulation of ER stress, WNK4-SPAK-NKCC1 cascades, inflammation and apoptosis. Cell viability was investigated by the CCK-8 assay. The expressions of the proteins were assessed by immunoblotting analysis assays. The levels of pro-inflammatory cytokines were determined by ELISA. The expression of cytoplasmic Ca2+ in A549 cells was determined using Fluo-4 AM. AEDS attenuates LPS-induced inflammation, which is associated with increased pro-inflammatory cytokine expression and activation of the WNK4-SPAK-NKCC1 pathway. AEDS inhibits the WNK4-SPAK-NKCC1 pathway by regulating of Bcl-2, IP3R and intracellular Ca2+. WNK4 expression levels are significantly higher in the WNK4-overexpressed transfected A549 cells and significantly decrease after AEDS treatment. AEDS attenuates LPS-induced inflammation by inhibiting the WNK4-SPAK-NKCC1 cascade. Therefore, AEDS is regarded as a potential therapeutic agent for ALI.

The Role of Bioactives in Inflammation.

As a physiological defense mechanism, inflammation is a complex response to harmful stimuli [...].

Zaxinone Synthase overexpression modulates rice physiology and metabolism, enhancing nutrient uptake, growth and productivity.

The rice Zaxinone Synthase (ZAS) gene encodes a carotenoid cleavage dioxygenase (CCD) that forms the apocarotenoid growth regulator zaxinone in vitro. Here, we generated and characterized constitutive ZAS-overexpressing rice lines, to better understand ZAS role in determining zaxinone content and regulating growth and architecture. ZAS overexpression enhanced endogenous zaxinone level, promoted root growth and increased the number of productive tillers, leading to about 30% higher grain yield per plant. Hormone analysis revealed a decrease in strigolactone (SL) content, which we confirmed by rescuing the high-tillering phenotype through application of a SL analogue. Metabolomics analysis revealed that ZAS overexpressing plants accumulate higher amounts of monosaccharide sugars, in line with transcriptome analysis. Moreover, transgenic plants showed higher carbon (C) assimilation rate and elevated root phosphate, nitrate and sulphate level, enhancing the tolerance towards low phosphate (Pi). Our study confirms ZAS as an important determinant of rice growth and architecture and shows that ZAS regulates hormone homoeostasis and a combination of physiological processes to promote growth and grain yield, which makes this gene an excellent candidate for sustainable crop improvement.

Optical ReLU-like activation function based on a semiconductor laser with optical injection.

Artificial neural networks usually consist of successive linear multiply-accumulate operations and nonlinear activation functions. However, most optical neural networks only achieve the linear operation in the optical domain, while the optical implementation of activation function remains challenging. Here we present an optical ReLU-like activation function (with 180° rotation) based on a semiconductor laser subject to the optical injection in an experiment. The ReLU-like function is achieved in a broad regime above the Hopf bifurcation of the injection-locking diagram and is operated in the continuous-wave mode. In particular, the slope of the activation function is reconfigurable by tuning the frequency difference between the master laser and the slave laser.

Optomechanical Frequency Comb Based on Multiple Nonlinear Dynamics.

Phonon-based frequency combs that can be generated in the optical and microwave frequency domains have attracted much attention due to the small repetition rates and the simple setup. Here, we experimentally demonstrate a new type of phonon-based frequency comb in a silicon optomechanical crystal cavity including both a breathing mechanical mode (∼GHz) and flexural mechanical modes (tens of MHz). We observe strong mode competition between two approximate flexural mechanical modes, i.e., 77.19 and 90.17 MHz, resulting in only one preponderant lasing, while maintaining the lasing of the breathing mechanical mode. These simultaneous observations of two-mode phonon lasing state and significant mode competition are counterintuitive. We have formulated comprehensive theories to elucidate this phenomenon in response to this intriguing outcome. In particular, the self-pulse induced by the free carrier dispersion and thermo-optic effects interacts with two approximate flexural mechanical modes, resulting in the repetition rate of the comb frequency-locked to exact fractions of one of the flexural mechanical modes and the mode hopping between them. This phonon-based frequency comb has at least 260 comblines and a repetition rate as low as a simple fraction of the flexural mechanical frequency. Our demonstration offers an alternative optomechanical frequency comb for sensing, timing, and metrology applications.

Knowledge of and policy support for the SDGs: An inverted U-shaped relationship.

This study aims to examine the relationship between knowledge of the SDGs and public policy support for the SDGs. By categorizing knowledge into objective and subjective knowledge, we examine the impact of these two types of knowledge on public support. And we further explores the moderating role of public trust in international/environmental organizations and the mediating role of individuals' perceptions of SDGs' relevance. By conducting an online survey in China (n=3089), we analyze the dataset using (generalized) logistic regression model and mediation analysis. This study finds that 1) both individuals' objective and subjective knowledge of SDGs are significantly associated with policy support for SDGs, an inverted U-shaped relationship is identified for objective knowledge, while subjective knowledge and policy support are positively correlated; 2) for publics who trust international/environmental organizations, their support for the SDGs will be boosted by their increased level of knowledge; 3) individuals' perceptions of SDGs' relevance to their personal life mediates the relationship between individual's knowledge of SDGs and policy support for the SDGs. This study applies several sampling and modelling techniques for robustness check. This study extends our understanding of the relationship between knowledge and policy support in the context of the SDGs.

Synthesis and Biological Evaluation of Novel Piperidine-3-Carboxamide Derivatives as Anti-Osteoporosis Agents Targeting Cathepsin K.

A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound H-9 exhibited the most potent inhibition, with an IC50 value of 0.08 µM. Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that H-9 effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.

Oncology social workers' involvement in palliative care: Secondary data analysis from nationwide oncology social workers survey.

OBJECTIVES: Social workers are vital in delivering psychosocial services in palliative care, yet their specific roles in palliative oncology remain undefined. This study aimed to delineate the current practice role of oncology social workers involvement in palliative care in the United States. METHODS: This study utilized a cross-sectional design and involved secondary analysis of data from a nationwide survey focused on workforce conditions for oncology social workers. The participants were social workers who were directly involved in providing care to cancer patients and delivering palliative care services. They completed an online survey in which they indicated the relevance of 91 tasks related to their practice. The survey also collected individual demographic and work-related characteristics. Exploratory factor analysis was used to achieve the study objective. RESULTS: Responses from a secondary data set of 243 oncology social workers involved in palliative care results in a 6-factor solution comprising 34 tasks. These factors were identified as: Therapeutic Interventions for Individuals, Couples, and Families; Facilitate Patient Care Decision-making; Care Coordination; Assessment and Emotional Support; Organization and Community Service; and Equity and Justice. All 6 factors demonstrated good internal reliability, as indicated by Cronbach's alpha scores above 0.70. SIGNIFICANCE OF RESULTS: The findings can be used to develop job descriptions and education for social workers employed in palliative cancer care. The clear role descriptions also make social work visible to other professionals in palliative oncology. By clarifying the roles of oncology social workers, this study contributes to the improvement of palliative care delivery and enhances interprofessional collaboration within cancer care teams.

Bioactives and Inflammation.

Inflammation is one of the body's most complex physiological defense mechanisms against harmful substances [...].

Rational Design of a High-Loading Polysulfide Cathode and a Thin-Lithium Anode for Developing Lean-Electrolyte Lithium-Sulfur Full Cells.

Lithium-sulfur cells are attractive energy-storage systems because of their high energy density and the electrochemical utilization rates of the high-capacity lithium-metal anode and the low-cost sulfur cathode. The commercialization of high-performance lithium-sulfur cells with high discharge capacity and cyclic stability requires the optimization of practical cell-design parameters. Herein, a carbon structural material composed of a carbon nanotube skeleton entrapping conductive graphene is synthesized as an electrode substrate. The carbon structural material is optimized to develop a high-loading polysulfide cathode with a high sulfur loading capacity (6-12 mg cm-2 ), rate performance (C/10-C/2), and cyclic stability for 200 cycles. A thin lithium anode based on the carbon structural material is developed and exhibits long lithium stripping/plating stability for ≈2500 h with a lithium-ion transference number of 0.68. A lean-electrolyte lithium-sulfur full cell with a low electrolyte-to-sulfur ratio of 6 µL mg-1 is constructed with the designed high-loading polysulfide cathode and the thin lithium anode. The integration of all the critical cell-design parameters endows the lithium-sulfur full cell with a low negative-to-positive capacity ratio of 2.4, while exhibiting stable cyclability with an initial discharge capacity of 550 mAh g-1 and 60% capacity retention after 200 cycles.

Magnonic Frequency Comb in the Magnomechanical Resonator.

An optical frequency comb is a spectrum of optical radiation which consists of evenly spaced and phase-coherent narrow spectral lines and is initially invented in a laser for frequency metrology purposes. A direct analog of frequency combs in the magnonic systems has not been demonstrated to date. In our experiment, we generate a new magnonic frequency comb in the resonator with giant mechanical oscillations through the magnomechanical interaction. We observe the magnonic frequency comb contains up to 20 comb lines, which are separated by the mechanical frequency of 10.08 MHz. The thermal effect based on the strong pump power induces the cyclic oscillation of the magnon frequency shift, which leads to a periodic oscillation of the magnonic frequency comb. Moreover, we demonstrate the stabilization and control of the frequency spacing of the magnonic frequency comb via injection locking. Our Letter lays the groundwork for magnonic frequency combs in the fields of sensing and metrology.

Illness uncertainty and quality of life in patients with advanced cancer and their family caregivers: An actor-partner interdependence model analysis.

OBJECTIVE: The relationship between illness uncertainty and quality of life (QOL) has been examined for either the patient or caregiver, but not among the patient-caregiver dyads. This study examined relationships between illness uncertainty and QOL among patients with advanced cancer and family caregivers. METHODS: We conducted a secondary analysis of data from a randomized clinical trial that examined the effects of a dyadic-based intervention on psychological outcomes for patients with advanced cancer and family caregivers (N = 484 dyads). Illness uncertainty and QOL were measured using the shorten version of the Mishel Uncertainty in Illness Scale for Adult and the Functional Assessment of Cancer Therapy, respectively. The actor-partner interdependence model was used to examine whether an individual's uncertainty (either a patient's or caregiver's) was associated with their own QOL (i.e., an actor effect) and/or their partner's QOL (i.e., a partner effect). RESULTS: Significant actor effects included a negative association between patients' uncertainty and their own QOL (b = -0.422; p < 0.001) and a negative association between caregivers' uncertainty and their own QOL (b = -0.408; p < 0.001). In terms of partner effects, patients' uncertainty was negatively associated with caregivers' QOL (b = -0.095; p < 0.01). No partner effect was found for caregivers, suggesting that caregivers' uncertainty was not related to patients' QOL. CONCLUSIONS: Study findings support targeted interventions offered to both patients and their family caregivers to manage their illness uncertainty and improve their QOL.

Novel xanthone antibacterials: Semi-synthesis, biological evaluation, and the action mechanisms.

α-Mangostin (α-MG) has demonstrated to display potent activities against Gram-positive bacterial. However, the contribution of phenolic hydroxyl groups of α-MG to the antibacterial activity remains obscure, severely hampering selection of structure modification to develop more potential α-MG-based anti-bacterial derivatives. Herein, twenty-one α-MG derivatives are designed, synthesized and evaluated for the antibacterial activities. The structure activity relationships (SARs) reveal that the contribution of the phenolic groups ranks as C3 > C6 > C1, and the phenolic hydroxyl group at C3 is essential to the antibacterial activity. Of note, compared to the parent compound α-MG, 10a with one acetyl at C1 exhibits the higher safety profiles due to its higher selectivity and no hemolysis, and the more potent antibacterial efficacy in an animal skin abscess model. Our evidences further present that, in comparison with α-MG, 10a has a stronger ability in depolarizing membrane potentials and leads to more leakage of bacterial proteins, consistent with the results observed by transmission electron microscopy (TEM). Transcriptomics analysis demonstrates those observations possibly relate to disturbed synthesis of proteins participating in the biological process of membrane permeability and integrity. Collectively, our findings provide a valuable insight for developing α-MG-based antibacterial agents with little hemolysis and new action mechanism via structural modifications at C1.

Correlates of illness uncertainty in cancer survivors and family caregivers: a systematic review and meta-analysis.

PURPOSE: Illness uncertainty is widely recognized as a psychosocial stressor for cancer survivors and their family caregivers. This systematic review and meta-analysis aimed to identify the sociodemographic, physical, and psychosocial correlates that are associated with illness uncertainty in adult cancer survivors and their family caregivers. METHODS: Six scholarly databases were searched. Data synthesis was based on Mishel's Uncertainty in Illness Theory. Person's r was used as the effect size metric in the meta-analysis. Risk of bias was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. RESULTS: Of 1116 articles, 21 articles met the inclusion criteria. Of 21 reviewed studies, 18 focused on cancer survivors, one focused on family caregivers, and 2 included survivors and family caregivers. Findings identified distinct correlates for illness uncertainty in cancer survivors, including sociodemographic factors (e.g., age, gender, race), stimuli frame (e.g., symptom, family history of cancer), structure providers (e.g., education), coping, and adaptation. Notable effect sizes were observed in the correlations between illness uncertainty and social support, quality of life, depression, and anxiety. Caregivers' illness uncertainty was associated with their race, general health, perception of influence, social support, quality of life, and survivors' prostate-specific antigen levels. Insufficient data precluded examining effect size of correlates of illness uncertainty among family caregivers. CONCLUSION: This is the first systematic review and meta-analysis to summarize the literature on illness uncertainty among adult cancer survivors and family caregivers. Findings contribute to the growing literature on managing illness uncertainty among cancer survivors and family caregivers.

Proactive therapeutic drug monitoring of vincristine in pediatric and adult cancer patients: current supporting evidence and future efforts.

Vincristine (VCR), an effective antitumor drug, has been utilized in several polytherapy regimens for acute lymphoblastic leukemia, neuroblastoma and rhabdomyosarcoma. However, clinical evidence shows that the metabolism of VCR varies greatly among patients. The traditional based body surface area (BSA) administration method is prone to insufficient exposure to VCR or severe VCR-induced peripheral neurotoxicity (VIPN). Therefore, reliable strategies are urgently needed to improve efficacy and reduce VIPN. Due to the unpredictable pharmacokinetic changes of VCR, therapeutic drug monitoring (TDM) may help to ensure its efficacy and to manage VIPN. At present, there is a lot of supporting evidence for the suitability of applying TDM to VCR therapy. Based on the consensus guidelines drafted by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), this review aimed to summarize various available data to evaluate the potential utility of VCR TDM for cancer patients. Of note, valuable evidence has accumulated on pharmacokinetics variability, pharmacodynamics, drug exposure-clinical response relationship, biomarkers for VIPN prediction, and assays for VCR monitoring. However, there are still many relevant clinical pharmacological questions that cannot yet be answered merely based on insufficient evidence. Currently, we cannot recommend a therapeutic exposure range and cannot yet provide a dose-adaptation strategy for clinicians and patients. In areas where the evidence is not yet sufficient, more research is needed in the future. The precision medicine of VCR cannot rely on TDM alone and needs to consider the clinical, environmental, genetic background and patient-specific factors as a whole.

Untargeted metabolomic profiling identifies disease-specific and outcome-related signatures in chronic rhinosinusitis.

BACKGROUND: Although metabolomics provides novel insights into disease mechanisms and biomarkers, the metabolic alterations in local tissues affected by chronic rhinosinusitis (CRS) are unknown. OBJECTIVE: This study aimed to determine the metabolomic profiles of sinonasal tissues associated with different types of CRS and their treatment outcomes. METHODS: Untargeted metabolomic profiling was performed on sinonasal tissues obtained from patients with eosinophilic CRS with nasal polyps (CRSwNP), noneosinophilic CRSwNP or CRS without nasal polyps (CRSsNP), and controls. The messenger RNA (mRNA) levels of inflammatory cytokines in nasal tissues were detected by quantitative real-time reverse transcriptase PCR. Nasal polyp tissues were cultured ex vivo and treated with glutathione. RESULTS: Distinct metabolomic profiles were observed for the CRS subtypes. Eosinophilic CRSwNP had profoundly enhanced unsaturated fatty acid oxidization, which correlated with mucosal eosinophil numbers and IL-5 mRNA levels. Noneosinophilic CRSwNP was characterized by uric acid accumulation. Increased uric acid levels were positively correlated with mucosal neutrophil numbers and IFN-γ, IL-17A, IL-1ß, and IL-8 mRNA levels. Disrupted purine metabolism was specifically detected in CRSsNP. Reduced levels of amino acid metabolites were found in eosinophilic CRSwNP and CRSsNP, and were inversely associated with mucosal total inflammatory cell numbers and inflammatory cytokines. Compared to non-difficult-to-treat CRS, difficult-to-treat CRS had higher glutathione disulfide levels, which were positively correlated with IL-8 mRNA levels. Glutathione treatment reduced IL-8 mRNA expression in cultured nasal polyp tissues. CONCLUSIONS: Specific metabolic signatures are associated with different types of CRS, inflammatory patterns, and disease outcomes, which may provide novel insights into pathophysiologic mechanisms, subtype-specific biomarkers, and treatment targets of CRS.